Combination of Metformin to Neoadjuvant Radiochemotherapy in the Treatment of Locally Advanced Rectal Cancer.

Patients eligible for the trial and having signed their consent to participate will undergo a dosimetric scan at baseline. 48 hours later (minimum), a Metformin therapy will be started at a dosage of 850 mg 2 times / day ( = 1700 mg / day). Seven days later (minimum) and up to 48 hours before surgery, the dosage of Metformin will be increased to 850 mg 3 times / day ( = 2550 mg / day). This very same day (J10), patients will start a radiochemotherapy. For 5 weeks, 5 days out of 7, patients will receive 800 mg/m² of Capecitabine 2 times / day (on morning and evening) ( = 1600 mg / m² / day) and a 3D irradiation or an Intensity-Modulated Radiation Therapy (IMRT) of a total dose of 50 Gy (5 sessions of 2 Gy per week). 6 to 8 weeks after completion of the chemoradiotherapy, surgery will be scheduled. It will consist of a tumor resection with total resection of the meso rectum.

Prior to the start of treatment, patients will have a clinical and a paraclinical examination and will undergo a laboratory examination. Once a week during the radiochemotherapy, patients will have a clinical examination and will undergo a laboratory examination. Three weeks after the end of the radiochemotherapy, patients will have a clinical examination. Before surgery, patients will have a clinical and a paraclinical examination. Finally, at the end of the study, patients will have a clinical examination.

Inclusion criteria

• Patient with an adenocarcinoma of the low or middle rectum.
• T3 or T4 stage (T evaluated by MRI and / or echo-endoscopy).
• Absence of distant metastasis.
• Patient requiring a radiochemotherapy.
• Correct hematological conditions : Neutrophils ≥ 1500 G / L, platelets ≥ 100 000 G / L.
• Age ≥ 18 years
• Performance status (WHO) ≤ 2
• Lactatemia ≤ Higher standard of the sampling laboratory.
• For women of childbearing age, a contraceptive method is mandatory for the entire duration of the study.

Exclusion criteria

• Other histologies such as squamous cell carcinoma, neuroendocrine tumors, melanomas, etc.
• History of lactic acidosis.
• Any diabetes (According to the WHO definition : fasting plasma glucose (FPG) > 1.26 g / L-1).
• Ongoing antidiabetic treatment such as

• Biguanides, hypoglycemic sulfamides, glinides, GLP-1 analogue, gliptins, alpha-glucosidase inhibitors
• Insulin or insulin analogues
• Hypersensitivity to capecitabine or to any of the excipients or to fluorouracil.
• History of severe and unexpected reactions to a fluoropyrimidine therapy.
• Patient with known deficiency to the dihydropyrimidine dehydrogenase (DPD).
• Hypersensitivity to metformin or to any of the excipients.
• Renal failure or impaired renal function (creatinine clearance < 60 ml / min).
• Severe infection.
• Acute or chronic disease which may cause tissue hypoxia such as heart or respiratory failure or recent myocardial infarction (< 6 months).
• Hepatic insufficiency, acute alcohol intoxication, alcoholism.
• Psychiatric inability to give consent.
• Contraindication to radiation therapy and/or chemotherapy.
• Treatment with sorivudine or its chemically related analogues, such as brivudine.
• Patient under tutorship or guardianship.
• Pregnant or breastfeeding women.